4-(Substituted-amino)-2-(pyridinyl) pyrimidine derivatives

ABSTRACT

Compounds useful as anti-allergic agents are 2-Q-4-[XZC=C(R)NH]-5-R 1  -6-R 2  -pyrimidines (I), where Q is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents or N-oxide thereof, R is hydrogen or lower-alkyl, R 1  is hydrogen, lower-alkyl or cyano, R 2  is hydrogen, lower-alkyl, hydroxy or halo, X and Z are the same or different and are each selected from lower-carbalkoxy, lower-alkanoyl, carbamyl and cyano, or ##STR1## is ##STR2## wherein R 3  and R 4  are each lower-alkyl, or X is hydrogen, are prepared by reacting 4-amino-2-Q-5-R 1  -6-R 2  -pyrimidine (II where Q&#39; is amino) with R&#39;O-C(R)=CXZ (III). Preparations of II are given. Also shown as intermediates and/or anti-allergic agents are 4-(AcNH)-2-Q-5-R 1  -6-R 2  -pyrimidines (IV) and 4-(R 5  R 6  N)-2-Q-5-R 1  -6-R 2  -pyrimidines (V) where Ac is lower-alkanoyl or lower-carbalkoxy, R 5  is hydrogen, lower-alkyl or lower-hydroxyalkyl, and R 6  is lower-alkyl or lower-hydroxyalkyl.

CROSS-REFERENCE TO RELATED APPLICATIONS

Certain of the di-(lower-alkyl) N-(2-Q-6-R₂-4-pyrimidinyl)aminomethylenemalonates (I where R and R₁ are eachhydrogen and X and Y are each lower-carbalkoxy) disclosed and claimed incopending application Ser. No. 555,067, filed Mar. 3, 1975, now U.S.Pat. No. 4,018,770, issued Apr. 19, 1977, are disclosed as intermediatesin the preparation of antibacterially active5,8-dihydro-5-oxopyrido[2,3-d]pyrimidines which are disclosed andclaimed in U.S. patent application Ser. No. 555,051, filed Mar. 3, 1975,now U.S. Pat. No. 3,992,380 issued Nov. 16, 1976.

This application is a division of copending application Ser. No.708,195, filed July 23, 1976, now U.S. Pat. No. 4,032,523, issued June28, 1977, which in turn is a division of said copending application Ser.No. 555,067, filed Mar. 3, 1975.

BACKGROUND OF THE INVENTION

a. Field of the Invention

This invention relates to pyrimidinylaminomethylenemalonate derivativesand analogs which are useful as anti-allergic agents, and tointermediates and processes for their preparation.

B. Description of the Prior Art

The Sterling Drug Inc. Lesher U.S. Pat. No. 3,320,257, issued May 16,1967, discloses, inter alia, dialkyl N-(2-R₂ -6-R₄-4-pyrimidinyl)aminomethylenemalonates where R₂ and R₄ are eachhydrogen, lower-alkyl, lower-alkoxy, lower-alkylamino,lower-alkylmercapto, phenylmethyl, phenyloxy, phenylamino orphenylmercapto. The compounds are shown to be useful as intermediatesfor preparing anti-bacterially active 5,8-dihydro-8-(lower-alkyl)-2-R₂-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acids.

The Dainippon Pharmaceutical Co., Ltd. British Patent Specification No.1,129,358, published Oct. 2, 1968, discloses as intermediates forpreparing antibacterially active5,8-dihydro-5-oxopyrido[2,3-d]pyrimidines certain N-[2-R₃ -6-R₂-4-pyrimidinyl]aminomethylenemalonates where R₂ is hydrogen, a loweralkyl radical, a hydroxy group, a halogen atom, a lower alkoxy radical,an amino group or a lower alkylthio radical and R₃ is hydrogen, a loweralkyl radical, a hydroxy group, a lower alkoxy radical, a loweralkylthio group or a radical of formula ##STR3## (in which R' ishydrogen, an alkyl radical, a cycloalkyl radical, an amino group, ahydroxyalkyl radical or an alkyl-substituted aminoalkyl radical, R" ishydrogen or an alkyl radical or R' and R", together with the nitrogenatom to which they are bonded, form a heterocyclic ring).

SUMMARY OF THE INVENTION

In one composition aspect, the invention relates to certainN-[2-(pyridinyl)-5-R₁ -6-R₂ -4-pyrimidinyl]aminomethylenemalonates andanalogs (I), which are useful as anti-allergic agents.

In another composition aspect, the invention relates to 2-Q-4-Q'-5-R₁-6-R₂ -pyrimidines (II) which are useful as intermediates in thepreparation of the above final products (I), and some of which areuseful as anti-allergic agents.

The invention in a process aspect comprises reacting a compound offormula II where Q' is amino with a compound of the formula R'O-C(R)═CXZto produce the compound of formula I.

In another composition aspect, the invention relates to 2-Q-4-AcNH-5-R₁-6-R₂ -pyrimidines (IV) which are useful as intermediates and some asanti-allergic agents.

In another composition aspect, the invention relates to 2-Q-4-R₅ R₆N-5-R₁ -6-R₂ -pyrimidines (V) which are useful as anti-allergic agents.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

The invention in a composition aspect resides in the compounds havingformula I ##STR4## where Q is 4- or 3- or 2-pyridinyl or 4- or 3- or2-pyridinyl having one or two lower-alkyl substituents of N-oxidethereof, R is hydrogen or lower-alkyl, R₁ is hydrogen, lower-alkyl orcyano, R₂ is hydrogen, lower-alkyl, hydroxy or halo, X and Z are thesame or different and are each selected from lower-carbalkoxy,lower-alkanoyl, carbamyl and cyano or ##STR5## is ##STR6## where R₃ andR₄ are each lower-alkyl, or X is hydrogen. The compounds of formula Iare useful as anti-allergic agents, as determined by standardpharmacological evaluation procedures. Preferred embodiments are thosehaving formula I where R, R₁ and R₂ are each hydrogen, X and Z are eachlower-carbalkoxy and Q is 4(or 3)-pyridinyl, particularly preferredembodiments being those where X and Z are each carbomethoxy (COOCH₃) orcarbethoxy (COOC₂ H₅). The compounds of formula I where Q is 4(or3)-pyridinyl or 4(or 3)-pyridinyl having one or two lower-alkylsubstituents, R₂ is hydrogen or lower-alkyl, R and R₁ are each hydrogen,and X and Z are each lower-carbalkoxy are disclosed as intermediates forpreparing lower-alkyl 5,8-dihydro-5-oxo-2-Q-4-R₂-pyrido[2,3-d]pyrimidine-6-carboxylates and corresponding1-(lower-alkyl)-6-carboxylic acids in application Ser. No. 555,051,filed Mar. 3, 1975, now U.S. Pat. No. 3,992,380, issued Nov. 16, 1976.

The invention in another composition aspect resides in the compoundshaving formula II ##STR7## where Q, R₁ and R₂ have the meanings givenabove for formula I and Q' is hydroxy, halo, hydrazino (NHNH₂) or amino(NH₂). These compounds are useful in the preparation of the compounds offormula I and other than the compounds where Q' is halo also are usefulas anti-allergic agents. The compounds of formula II are disclosed andclaimed in said U.S. Pat. No. 4,032,523.

The invention in a process aspect comprises reacting a compound offormula II where Q' is amino with a compound of the formula III ##STR8##to produce the compound of formula I, where R' is lower-alkyl, and R, Xand Z each is defined as given above for formula I and, optionally,reacting I where Q represents other than a pyridinyl N-oxide with anoxidizing agent capable of converting pyridines to pyridine-N-oxides toproduce the corresponding compounds (I) where Q is a pyridinyl N-oxide.

The invention in another composition aspect resides in the compoundshaving formula IV ##STR9## where Q, R₁ and R₂ have the meanings givenabove for formula I and Ac is lower-alkanoyl or lower-carbalkoxy. Thesecompounds, as shown hereinbelow, are useful as intermediates in thepreparation of the compounds of formula II where Q' is amino and Q is apyridinyl N-oxide. Also, compounds of formula IV where Ac islower-carbalkoxy are useful as anti-allergic agents.

The invention in another composition aspect resides in the compoundshaving formula V ##STR10## where Q, R₁ and R₂ have the meanings givenabove for formula I, R₅ is hydrogen, lower-alkyl or lower-hydroxyalkyland R₆ is lower-alkyl or lower-hydroxyalkyl, which are useful asanti-allergic agents.

The term "lower-alkyl" as used herein, e.g., as one of the meanings forR, R₁ or R₂ or as a substituent for Q in formulas I, II, III, IV or V,means alkyl radicals having from one to six carbon atoms which can bearranged as straight or branched chains, illustrated by methyl, ethyl,n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, n-amyl,n-hexyl, and the like.

The term "lower-carbalkoxy", as used herein, e.g., as one of themeanings for X or Z in formula I or III or as one of the meanings for Acin formula IV, means carbalkoxy radicals where the alkoxy portion can bestraight- or branch-chained and has from one to six carbon atoms, asillustrated by carbomethoxy, carbethoxy, carbo-n-propoxy,carbisopropoxy, carbo-n-butoxy, carbo-tert.-butoxy and carbo-n-hexoxy.

Illustrative of the Q substituent in formulas I or II where Q is 4(3 or2)-pyridinyl having one or two lower-alkyl substituents are thefollowing [note that "pyridinyl" as used herein is the same as"pyridyl", the former now being the preferred term used in ChemicalAbstracts]: 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl,3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl(alternatively named 2-methyl-5-pyridinyl) 4-methyl-2-pyridinyl,6-methyl-2-pyridinyl, 2,3-dimethyl-4-pyridinyl,2,5-dimethyl-4-pyridinyl, 4,6-dimethyl-2-pyridinyl, 2-ethyl-4-pyridinyl,2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl,2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl,2,6-di-isopropyl-4-pyridinyl, 2,6-di-n-hexyl-4-pyridinyl, and the like.

The term "lower-alkanoyl", as used herein, e.g., as one of the meaningsfor X and Z in formulas I and III and as one of the meanings for Ac informula IV, means alkanoyl radicals having from two to six carbon atoms,including the straight- and branch-chained radicals, illustrated byacetyl, propionyl (n-propanoyl), butyryl (n-butanoyl), isobutyryl(2-methyl-n-propanoyl) and caproyl (n-hexanoyl).

The term "lower-hydroxyalkyl", as used herein, e.g., as one of themeanings for R₅ and R₆ in formula V, means hydroxyalkyl radicals havingfrom two to six carbon atoms and having its hydroxy group and its freevalence bond (or connecting linkage) on different carbon atoms,illustrated by 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,2-hydroxy-2-methylpropyl, 3-hydroxypropyl, 4-hydroxybutyl,5-hydroxyamyl, 6-hydroxyhexyl, 2-hydroxy-1,1-dimethylethyl, and thelike.

Also, the compounds of formula I and formula II where Q' is amino orhydrazino are useful both in the free base form and in the form ofacid-addition salts; and, both forms are within the purview of theinvention. The acid-addition salts are simply a more convenient form foruse; and in practice, use of the salt form inherently amounts to use ofthe base form. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, medicinally acceptable salts, that is, salts whose anions arerelatively innocuous to the animal organism in medicinal doses of thesalts, so that the beneficial anti-allergic properties inherent in thefree base are not vitiated by side effects ascribable to the anions. Inpracticing the invention, it was found convenient to form thehydrochloride, methanesulfonate or cyclohexylsulfamate salts. However,other appropriate medicinally acceptable salts within the scope of theinvention are those derived from mineral acids such as phosphoric acid,sulfamic acid, and sulfuric acid; and organic acids such as acetic acid,citric acid, tartaric acid, lactic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, quinic acid, and the like,giving the phosphate, sulfamate, acetate, citrate, tartrate, lactate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and quinate,respectively.

The acid-addition salts of said basic compounds are prepared either bydissolving the free base in aqueous or aqueous-alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and acid in an organicsolvent, in which case the salt separates directly or can be obtained byconcentration of the solution.

Although medicinally acceptable salts of said basic compounds arepreferred, all acid-addition salts are within the scope of ourinvention. All acid-addition salts are useful as sources of the freebase form even if the particular salt per se is desired only as anintermediate product as for example when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a medicinally acceptable salt by ion exchangeprocedures.

The molecular structures of the composition aspects (I and II) of theinvention were assigned on the basis of evidence provided by infrared,ultraviolet, nuclear magnetic resonance and mass spectra, bychromatographic mobilities, and, by the correspondence of calculated andfound values for the elementary analyses for representative examples.

The manner of making and using the instant invention will now begenerally described so as to enable a person skilled in the art ofchemistry to make and use the same, as follows:

The preparation of the compounds of formula I is carried out by reactinga 4-amino-2-Q-5-R₁ -6-R₂ -pyrimidine (formula II where Q' is amino)where Q, R₁ and R₂ have the meanings given above for formula I, with acompound of formula III, i.e., R'O-C(R)═CXZ, where R', R, X and Z havethe meanings given for formula III. This reaction is carried out byheating said reactants, preferably in a molar ratio of 1:1 andpreferably with stirring, either in the absence or presence of asuitable inert solvent, at about 100° C. to 200° C., preferably about120° C. to 160° C. The reaction is conveniently run by heating thereactants, either in refluxing xylene or in the absence of a solvent atthe said preferred heating temperature. Other suitable solvents inertunder the reaction conditions include toluene, anisole, nitrobenzene,chlorobenzene, dimethylformamide, dimethylacetamide, tetramethylurea,pyridine, α-picoline, β-picoline, γ-picoline, and the like.Alternatively, the above reaction can be carried out by preparing thereactant of formula III ##STR11## in situ without its actual isolationby heating a mixture of equimolar quantities of the compound of formulaII where Q' is amino, tri-(lower-alkyl) orthoformate, preferably thetriethyl ester, and a compound of formula VI ##STR12## where X and Zhave the meanings given for formulas I and III, under the reactionconditions discussed above. Preferably, the reaction is run in thepresence of a catalytic amount of an acidic catalyst, e.g., a stronginorganic acid such as hydrochloric acid, sulfuric acid, hydrobromicacid, phosphoric acid, and the like; an organic sulfonic acid such asp-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid,ethanesulfonic acid, and the like; a Lewis acid such as zinc chloride,boron trichloride, boron tribromide, aluminum trichloride; other strongorganic acid, e.g., trifluoroacetic acid, and the like.

The reaction of the compound of formula I where Q is other than apyridinyl N-oxide with an oxidizing agent to produce the compound offormula I where Q is a pyridinyl N-oxide is carried out by reactingcompound of formula I where Q is other than a pyridinyl N-oxide with anoxidizing agent capable of converting pyridines to pyridine N-oxides,preferably with a per acid, e.g., peracetic acid, perbenzoic acid,3-chloroperbenzoic acid, and the like, or with other oxidizing agents,e.g., hydrogen peroxide, in the presence of a suitable solvent inertunder the reaction conditions, e.g., acetic acid, chloroform, and thelike. The reaction is conveniently run by mixing the reactants carefullyat room temperature (about 20°-25° C.) up to about 40°-50° C.,preferably with stirring, and then heating the reaction mixture on asteam bath to ensure completion of the reaction.

The compounds of formula II are prepared by various procedures which areillustrated generally as follows and are further illustrated hereinbelowin the specific exemplary disclosure.

The preparation of the compounds of formula II where R₁ and R₂ are eachhydrogen and Q' is amino is conveniently carried out by heating apyridinecarboxamidine of the formula, Q-C(═NH)NH₂, with aβ-(lower-alkoxy)-acrylonitrile, preferably β-ethoxyacrylonitrile toproduce the 4-amino-2-Q-pyrimidine.

The preparation of the compounds of formula II where R₂ is lower-alkyland R₁ is hydrogen or lower-alkyl are readily produced by reacting apyridinecarboxamidine of the formula, Q-C(═NH)NH₂, with a lower-alkylβ-oxoalkanoate of the formula, R₂ -COCH(R₁)--COO--(lower-alkyl) toproduce 2-Q-5-R₁ -6-R₂ -4-pyrimidinol, reacting the 4-pyrimidinol with ahalogenating agent to produce 4-halo-2-Q-5-R₁ -6-R₂ -pyrimidine,reacting the 4-halo compound with hydrazine to produce4-hydrazino-2-Q-5-R₁ -6-R₂ -pyrimidine and catalytically hydrogenatingthe 4-hydrazino compound in the presence of a suitable catalyst, e.g.,Raney nickel, to produce 4-amino-2-Q-5-R₁ -6-R₂ -pyrimidine.

The preparation of the compounds of formula II where R₂ is hydrogen, R₁is methyl and Q' is amino is carried out by reacting apyridinecarboxamidine of the formula, Q-C(═NH)NH₂, withα-piperidinomethylacrylonitrile to produce4-amino-5-methyl-2-Q-pyrimidine. Optionally,α-piperidinomethylacrylonitrile can be replaced by otherα-[(BN)methyl]acrylonitriles where BN is lower-tertiary-amino such asdi-(lower-alkyl)amino, e.g., (CH₃)₂ N, (C₂ H₅)₂ N, and the like, orother saturated N-heteromonocyclic radicals, having 5 or 6 ring atoms,e.g., pyrrolidino, N-methylpiperazino, 2-methylpiperidino, and the like.

The preparation of the compounds of formula II where R₂ is hydrogen, R₁is cyano and Q' is amino is carried out by reacting apyridinecarboxamidine of the formula, Q-C(═NH)NH₂, with a(lower-alkoxy)methylenemalononitrile, preferablyethoxymethylenemalononitrile, to produce 4-amino-5-cyano-2-Q-pyrimidine.

The preparation of the compounds of formula II where R₂ is hydroxy orhydrogen, R₁ is hydrogen or lower-alkyl and Q' is amino are carried outby reacting a pyridinecarboxamidine of the formula, Q-C(═NH)NH₂, with acompound of the formula NC-CH(R₁)COO-(lower-alkyl) to produce4-amino-6-hydroxy-5-R₁ -2-Q-pyrimidine, halogenating this 6-hydroxycompound to produce 4-amino-6-halo-5-R₁ -2-Q-pyrimidine andcatalytically hydrogenating the 6-halo, preferably, 6-chloro compoundusing about 50 p.s.i. of hydrogen in the presence ofpalladium-on-charcoal catalyst to remove the halo substituent and toproduce 4-amino-5-R₁ -2-Q-pyrimidine.

The intermediate pyridinecarboxamidines of the formula, Q-C(═NH)NH₂, aregenerally known compounds which are prepared by conventional means.

The preparation of the compounds of formula II where Q' is amino and Qis a pyridinyl N-oxide are prepared by reacting the 4-acylaminocompounds of formula IV where Q is other than a pyridinyl N-oxide withan oxidizing agent capable of converting pyridines to pyridine-N-oxidesby the procedure described above for oxidizing the compounds of formulaI where Q is other than a pyridinyl N-oxide to produce the correspondingcompounds of formula I where Q is a pyridinyl N-oxide and thenhydrolyzing, as illustrated hereinbelow, the 4-acylamino-2-(pyridinylN-oxide) (IV) to produce the 4-amino-2-(pyridinyl N-oxide) (II).

The compound of formula IV where Q is other than a pyridinyl N-oxide isprepared by acylating the corresponding compound of formula II where Qis other than a pyridinyl N-oxide and Q' is amino, that is, by reactingthe said 4-amino compound (II) with a lower-alkanoylating agent or alower-carbalkoxylating agent, e.g., a lower-alkanoyl halide, preferablychloride, a lower-alkanoic anhydride, a lower-alkyl haloformate, and thelike, preferably in the presence of an acid acceptor, as illustratedhereinbelow.

The compound of formula V is prepared by reacting the compound offormula II where Q' is halo, preferably, chloro, with a primary amine R₆NH₂ or a secondary amine R₅ R₆ NH where R₆ and R₅ are defined as in V.This reaction is conveniently carried out in a lower-alkanol, with orwithout water; it is preferably run in refluxing ethanol orethanol-water.

The following examples will further illustrate the invention without,however, limiting it thereto.

A. 4-AMINO-2-(PYRIDINYL)PYRIMIDINES AND INTERMEDIATES

A-1. 4-Amino-2-(4-pyridinyl)pyrimidine - To an ice cold and stirredsolution of 172 g. of sodium methoxide in 800 ml. of methanol was slowlyadded 304 g. of isonicotinamidine dihydrochloride; the resulting mixturewas stirred for fifteen minutes and filtered. The inorganic residue waswashed with methanol and the filtrate plus washings were evaporated todryness in vacuo on a steam bath to yield 288 g. of isonicotinamidine infree base form. A mixture of said isonicotinamidine and 150 g. ofβ-ethoxyacrylonitrile was heated in an oil bath at 130°-150° C. forabout four hours, allowing the ethanol formed by the reaction to distilloff. The remaining material was dissolved in 200 ml. of concentratedhydrochloric acid and 100 ml. of water, and the solution allowed tostand overnight at room temperature (about 20°-25° C.). The solution wastreated with decolorizing charcoal, heated on a steam bath for 30minutes, filtered and the filtrate basified with ammonium hydroxide. Theresulting solid was collected, washed with cold water, air-dried,digested with hot methanol separated and air-dried to yield, as a tanpowder, 105 g. of 4-amino-2-(4-pyridinyl)pyrimidine, m.p. 260°-262° C.

The hydrochloride salt of 4-amino-2-(4-pyridinyl)pyrimidine was preparedas follows: a mixture containing 10 g. of4-amino-2-(4-pyridinyl)pyrimidine, 30 ml. of water and 20 ml. ofconcentrated hydrochloride acid was warmed to effect solution. To thewarm solution was added isopropyl alcohol to turbidity (about 110 ml.)whereupon crystals started to separate. The mixture was cooled and thecrystalline precipitate was collected, washed with isopropyl alcohol andether and dried in vacuo at 80° C. to yield 9.5 g. of4-amino-2-(4-pyridinyl)pyrimidine dihydrochloride as its monohydrate,m.p. 229° C. with decomposition.

A-2. 4-Amino-2-(3-pyridinyl)pyrimidine, m.p. 157°-159° C., 45 g., wasprepared following the procedure described in Example A-1 using 72 g. ofnicotinamidine dihydrochloride, 54 g. of sodium methoxide, 400 ml. ofmethanol, 60 g. of beta-ethoxyacrylonitrile and a heating period ofthree hours at 100°-125° C.

A-3. 6-Methyl-2-(4-pyridinyl)-4-pyrimidinol - A mixture containing 15.8g. of isonicotinamidine hydrochloride, 16.8 g. of sodium methoxide, 17g. of ethyl acetoacetate and 100 ml. of ethanol was refluxed withstirring for seven hours and then evaporated to dryness. The residue wasdissolved in water and the aqueous solution made acidic with aceticacid. The resulting solution was collected, washed with water, dried andrecrystallized from ethanol to yield 6.7 g. of6-methyl-2-(4-pyridinyl)-4-pyrimidinol, m.p. 236°-238° C.

A-4. 6-n-Propyl-2-(4-pyridinyl)-4-pyrimidinol - To an ice cooledsolution containing 500 ml. of methanol and 16 g. of sodium methoxidewas added 47.4 g. of isonicotinamidine hydrochloride; the mixture wasstirred for fifteen minutes and filtered to remove the precipitatedsodium chloride; the filtrate was concentrated in vacuo; 56 g. of ethylbutrylacetate was added; and the resulting mixture was heated in an oilbath at 160°-180° C. for three hours. After the reaction mixture hadbeen cooled, the separated product was collected and recrystallized fromethanol to yield 38.9 g. of 6-n-propyl-2-(4-pyridinyl)-4-pyrimidinol,m.p. 173°-174° C.

A-5. 4-Chloro-6-methyl-2-(4-pyridinyl)pyrimidine - A mixture containing26.5 g. of 6-methyl-2-(4-pyridinyl)-4-pyrimidinol, 27 g. ofphenylphosphonic dichloride and 75 ml. of phosphorus oxychloride wasrefluxed for four hours and then poured onto ice. The resulting aqueousmixture was made basic with ammonium hydroxide. The product wasextracted from the alkaline mixture using chloroform and the chloroformextract was concentrated in vacuo. The residue was filtered thru asilica gel column using ether as the solvent and eluent. Removal of theether yielded 12.9 g. of 4-chloro-6-methyl-2-(4-pyridinyl)pyrimidine,m.p. 128°-130° C.

A-6. 4-Hydrazino-6-methyl-2-(4-pyridinyl)pyrimidine - A solutioncontaining 36 g. of 4-chloro-6-methyl-2-(4-pyridinyl)pyrimidine, 100 ml.of ethanol and 20 ml. of hydrazine hydrate was refluxed on a steam bathfor two hours and then evaporated to dryness. The residue waspartitioned between water and chloroform. The chloroform layer wasseparated and the chloroform distilled off in vacuo to yield, as ayellow solid, 31.2 g. of 4-hydrazino-6-methyl-2-(4-pyridinyl)pyrimidine,m.p. 150°-152° C., which was used in the following step given in ExampleA-7. A 3.6 g. portion of this hydrazine was converted into itsdicyclohexylsulfamate salt which was recrystallized from ethanol toyield 7.2 g. of said salt, m.p. >280° C. with decomposition.

A-7. 4-Amino-6-methyl-2-(4-pyridinyl)pyrimidine - A mixture containing31 g. of 4-hydrazino-6-methyl-2-(4-pyridinyl)-pyrimidine, 150 ml. ofethanol and 2 g. of Raney nickel was shaken under hydrogen (48 p.s.i.)and heated to 63° C. whereupon there was an uptake of 10.7 lbs. ofhydrogen. The reaction mixture was cooled to room temperature and thecatalyst was filtered off. The filtrate was concentrated in vacuo toyield an orange solid that was crystallized from isopropyl alcohol toyield, as tan crystals, 22.6 g. of4-amino-6-methyl-2-(4-pyridinyl)pyrimidine, m.p. 192°-194° C.

A-8. 4-Amino-5-methyl-2-(4-pyridinyl)pyrimidine - A mixture containing15.8 g of isonicotinamidine hydrochloride, 100 ml. of ethanol, 5.4 g. ofsodium methoxide and 16.8 g. of α-(piperidinomethyl)acrylonitrile wasstirred at room temperature for two hours and then refluxed overnight(about sixteen hours). The reaction mixture was then cooled andevaporated to dryness in vacuo. The residue was diluted with water andthe solid was collected, washed with water and recrystallized fromisopropyl alcohol to yield 5.7 g. of4-amino-5-methyl-2-(4-pyridinyl)pyrimidine, m.p. 224°-226° C. It wascrystallized as its dimethanesulfonate, m.p. 210°-213° C., 6.5 g., bydissolving it in a minimum of hot isopropyl alcohol, adding 6.6 ml. ofmethanesulfonic acid, cooling the mixture, collecting the precipitatedsalt and drying it in vacuo at 80° C.

A-9. 4-Amino-2-(2-pyridinyl)pyrimidine - A mixture containing 12.2 g. of2-pyridinecarboxamidine in 9.8 g. of β-ethoxyacrylonitrile was heated inan oil bath at 150°-160° C. for 3 hours. The solid residue was taken upin boiling iospropyl alcohol, the hot solution treated with decolorizingcharcoal and filtered. To the hot filtrate was added 21 g. ofmethanesulfonic acid and the mixture chilled. The separated salt wasrecrystallized twice from isopropanol-ethanol and once from ethanol toyield 11.8 g. of 4-amino-2-(2-pyridinyl)-pyrimidine as itsdimethanesulfonate, m.p. 184°-186° C.

Following the procedure described in Example A-1 but using in place ofisonicotinamidine a molar equivalent quantity of the appropriatepyridine carboxamidine, i.e., Q-C(═NH)NH₂, the 4-amino-2-Q-pyrimidinesof Examples A-10 through A-13 are obtained:

A-10 . 4-Amino-2-(2-methyl-4-pyridinyl)pyrimidine using2-methylisonicotinamidine.

A-11. 4-Amino-2-(3-methyl-4-pyridinyl)pyrimidine using3-methylisonicotinamidine.

A-12. 4-Amino-2-(2-ethyl-4-pyridinyl)pyrimidine using2-ethylisonicotinamidine.

A-13. 4-Amino-2-(2,6-dimethyl-4-pyridinyl)pyrimidine using2,6-dimethylisonicotinamidine.

A-14. 4-Amino-2-(4pyridinyl)-6-pyrimidinol (alternatively named as6-amino-2-(4-pyridinyl)-4-pyrimidinol) - A mixture containing 15.6 g. ofisonicotinamidine hydrochloride, 11.3 g. ethyl cyanoacetate, 10.8 g. ofsodium methoxide and 100 ml. of ethanol was stirred at room temperaturefor 30 minutes and then refluxed for seven hours, followed byevaporation to dryness. To the residue was added 100 ml. of water andthe mixture was then acidified by adding acetic acid. The solid wascollected, dried in vacuo at 80° C. slurried in 100 ml. boiling ethanoland collected to yield 9.6 g. of 4-amino-2-(4-pyridinyl)-6-pyrimidinol,m.p. >350° C.

A-15. 4-Amino-2-(4-pyridinyl)-5-pyrimidinecarbonitrile - To a stirredsolution containing 15.8 g. of isonicotinamidine hydrochloride, 6 g. ofsodium methoxide and 200 ml. of methanol was added 14.2 g. ofethoxymethylenemalononitrile and the resulting mixture was stirred atroom temperature overnight (about sixteen hours). The solid wascollected, washed with water and recrystallized from methanol to yield20.7 g. of 4-amino-2-(4-pyridinyl)-5-pyrimidinecarbonitrile, m.p.253°-255° C.

A-16. N-[2-(4-Pyridinyl)-4-pyrimidinyl]acetamide - A mixture containing7 g. of 4-amino-2-(4-pyridinyl)pyrimidine, 25 ml. of pyridine and 10 ml.of acetic anhydride was allowed to stand at room temperature overnight,and then boiled on a hot plate until all of the solid had dissolved. Thereaction mixture was cooled to room temperature and poured onto ice.After the ice had melted, the white crystalline solid was collected,washed with water, dried in vacuo at 80° C. and recrystallized fromethanol to produce 3.8 g. of N-[2-(4-pyridinyl)-4-pyrimidinyl]acetamide,m.p. 218°-220° C.

A-17. N-[2-(4-Pyridinyl)-4-pyrimidinyl]hexanamide - A mixture containing4 g. of 4-amino-2-(4-pyridinyl)pyrimidine, 5 g. of n-hexanoyl chlorideand 50 ml. of pyridine was allowed to stand at room temperatureovernight and then poured onto the ice. After the ice had melted, 10 ml.of concentrated ammonium hydroxide was added and the cream colored solidwas collected, washed with water, dried in vacuo and recrystallized fromisopropyl alcohol to yield 6.2 g. ofN-[2-(4-pyridinyl)-4-pyrimidinyl]hexanamide, m.p. 119°-120° C.

A-18. 2-Methyl-N-[2-(4-pyridinyl)-4-pyrimidinyl]propanamide - A mixturecontaining 8.6 g. of 4-amino-2-(4-pyridinyl)pyrimidine, 50 ml. ofpyridine and 10 ml. of isobutyryl chloride was allowed to stand at roomtemperature overnight and then poured into ice cold water. The solid wascollected, washed with water, dried in vacuo at 80° C. andrecrystallized from ethanol to yield 7.9 g. of2-methyl-N-[2-(4-pyridinyl)-4-pyrimidinyl]propanamide, m.p. 215°-217° C.

A-19. n-Butyl N-[2-(4-pyridinyl)-4-pyrimidinyl]-carbamate - A mixturecontaining 9 g. of 4amino-2-(4-pyridinyl)-pyrimidine, 10 ml. of n-butylchloroformate and pyridine was kept in an ice bath for one hour and thenat room temperature overnight. The reaction mixture was then poured intoice cold water; the solid was collected, washed with water, dried invacuo at 80° C. and recrystallized from acetonitrile to yield 11.2 g. ofn-butyl N-[2-(4-pyridinyl)-4-pyrimidinyl]carbamate, m.p. 180°-182° C.

A-20. Ethyl N-[2-(4-pyridinyl)-4-pyrimidinyl]carbamate as itsmethanesulfonate, m.p. 198°-200° C., is obtained following the proceduredescribed in Example A-19 but using in place of n-butyl chloroformate amolar equivalent quantity of ethyl chloroformate, and recrystallizationfrom ethanol.

A-21. n-Butyl N-[2-(4-pyridinyl)-4-pyrimidinyl]carbamate N-Oxide [Itwill be appreciated, in view of the definition of Q in formula Ihereinabove, that N-oxide as used here and elsewhere in naming claimedcompounds of the invention means the N-oxide of the 2-pyridinyl)substituent, specifically the N-oxide of the 2-(4-pyridinyl) substituentin this Example A-21.] - To an ice cold solution containing 6 g. ofn-butyl N-[2-(4-pyridinyl)-4-pyrimidinyl]carbamate and 100 ml. ofchloroform was added 4.9 g. of 85% m-chloroperbenzoic acid and theresulting solution was allowed to stand at room temperature overnight.The excess acid was extracted with aqueous potassium carbonate and theremaining organic solution was collected to yield 5.8 g. of n-butylN-[2-(4-pyridinyl)-4-pyrimidinyl]carbamate N-oxide which was combinedwith 1.9 g. of the same compound prepared in another run and thecombined 7.7 g. of this compound was used without any furtherpurification in the following Example A-22.

A-22. 4-Amino-2-(4-pyridinyl)pyrimidine N-Oxide - A mixture containing7.7 g. of n-butyl N-[2-(4-pyridinyl)-4-pyrimidinyl]carbamate N-oxide, 50ml. of ethanol and 10 ml. of 35% aqueous sodium hydroxide solution wasallowed to stand at room temperature over the weekend and then wasrefluxed for four hours, concentrated in vacuo and the concentrateacidified with acetic acid. The mixture was heated on a steam bath andmade basic by adding ammonium hydroxide solution. The crystalline solidwas collected, washed with water, dried in vacuo at 80° C. andrecrystallized from dimethylformamide to yield 3.2 g. of4-amino-2-(4-pyridinyl)pyrimidine N-oxide, m.p. 317°-320° C.

4-Amino-2-(4-pyridinyl)-4-pyrimidine N-oxide also is prepared followingthe above procedure of Example A-22 but using in place of n-butylN-[2-(4-pyridinyl)-4-pyrimidinyl]carbamate N-oxide a molar equivalentquantity of N-[2-(4-pyridinyl)-4-pyrimidinyl]acetamide N-oxide or ethylN-[2-(4-pyridinyl)-4-pyrimidinyl]carbamate N-oxide.

A-23. N-(1,1-Dimethylethyl)-2-(4-pyridinyl)-4-pyrimidinamine[alternatively can be named4-tert.-butylamino)-2-(4-pyridinyl)pyrimidine] - A mixture containing10.2 g. of 4chloro-2-(4-pyridinyl)pyrimidine, 15 ml. of tert.-butylamineand 50 ml. of ethanol was refluxed for four hours and then concentratedin vacuo to remove the solvent and other volatile materials. The residuewas partitioned between chloroform and aqueous ammonium hydroxidesolution. The chloroform layer was separated and the chloroform removedin vacuo. The remaining residue was dissolved in ether containing 2 to5% (v/v) methanol and the solution was passed through a silica gelcolumn. The filtrate was evaporated in vacuo to remove the solvents andthe residue was crystallized from cyclohexane to yield 7.1 g. ofN-(1,1-dimethylethyl)-2-(4-pyridinyl)-4-pyrimidinamine, m.p. 202°-204°C.

A-24. N,N-Dimethyl-2-(4-pyridinyl)-4-pyrimidinamine - A mixturecontaining 6 g. of 4-chloro-2-(4-pyridinyl)pyrimidine, 10 ml of 70%aqueous dimethylamine and 50 ml. of ethanol was refluxed for four hoursand then evaporated to dryness. The residue was partitioned betweenaqueous sodium bicarbonate solution and chloroform. The chloroform layerwas separated dried over anhydrous magnesium sulfate, concentrated invacuo to remove the chloroform and the residue, and recrystallized fromcyclohexane to yield 4.8 g. ofN,N-dimethyl-2-(4-pyridinyl)-4-pyrimidinamine, m.p. 109°-110° C.

A-25. N,N,6-Trimethyl-2-(4pyridinyl)-4-pyrimidinamine as itsdihydrochloride monohydrate, m.p. 274°-276° C., 7.2 g. was preparedfollowing the procedure described in Example A-24 using 8 g. of4-chloro-6-methyl-2-(4-pyridinyl)pyrimidine, 15 ml. of 60% aqueousdimethylamine, 500 ml. of ethanol, a refluxing period of 2 hours andcrystallization of the dihydrochloride from ethanol.

A-26. N,6-Dimethyl-2-(4-pyridinyl)-4-pyrimidinamine, m.p. 145°-146° C.,7.6 g. was prepared following the procedure described in Example A-24using 8 g. of 4-chloro-6-methyl-2-(4-pyridinyl)pyrimidine, 15 ml. of 40%aqueous methylamine, 50 ml. of ethanol, a refluxing period of two hoursand recrystallization from ether-n-hexane.

A-27. 4-Amino-6-n-propyl-2-(4-pyridinyl)pyrimidine is prepared followingthe procedure described in Examples A-5, A-6 and A-7 starting with amolar equivalent quantity of 6-n-propyl-2-(4-pyridinyl)-4-pyrimidinol inplace of 6-methyl-2-(4pyridinyl)-4-pyrimidinol to produce respectively4-chloro-6-n-propyl-2-(4-pyridinyl)pyrimidine,4-hydrazino-6-n-propyl-2-(4-pyridinyl)pyrimidine and4-amino-6-n-propyl-2-(4-pyridinyl)-pyrimidine.

A-28. N-[2-(4-pyridinyl)-4-pyrimidinyl]acetamide N-Oxide is obtainedfollowing the procedure described in Example A-21 using a molarequivalent quantity of N-[2-(4-pyridinyl)-4-pyrimidinyl]acetamide inplace of n-butyl N-[2-(4-pyridinyl)-4-pyrimidinyl]carbamate.

A-29. Ethyl N-[2-(4-pyridinyl)-4-pyrimidinyl]carbamate N-Oxide isobtained following the procedure described in Example A-21 using a molarequivalent quantity of ethyl N-[2-(4-pyridinyl)-4-pyrimidinyl]carbamatein place of n-butyl N-[2-(4-pyridinyl)-4-pyrimidinyl]carbamate.

Following the procedure described in Example A-23 using in place oftert.-butylamine a molar equivalent quantity of the appropriate amine ofthe formula NHR₅ R₆, the compounds of Examples A-30 through A-33 areobtained:

A-30. N,N-Dimethyl-2-(4-pyridinyl)-4-pyrimidinamine using diethylamine.

A-31. N-Ethyl-2-(4-pyridinyl)-4-pyrimidinamine using ethylamine.

A-32. N,N-bis(2-Hydroxyethyl)-2-(4-pyridinyl)-4-pyrimidinamine usingbis(2-hydroxyethyl)amine.

A-33. N-(2-Hydroxyethyl)-2-(4-pyridinyl)-4-pyrimidinamine using2-hydroxyethylamine.

A-34. N,N-Diethyl-6-methyl-2-(4-pyridinyl)-4-pyrimidinamine - A mixturecontaining 8.2 g. of 4-chloro-6-methyl-2-(4-pyridinyl)pyrimidine, 8.7 g.of diethylamine hydrochloride, 100 ml. of ethanol, 6 g. of potassiumcarbonate and 10 ml. of water was refluxed with stirring for eight hoursand then concentrated in vacuo to dryness. The residue was swirled inwater and the solid collected. The solid was dissolved in boilingisopropyl alcohol, the hot solution treated with decolorizing charcoaland filtered, and the hot filtrate allowed to cool. The filtrate wasthen saturated with gaseous hydrogen chloride, ether was added toturbidity and the mixture was allowed to stand. The separated solid wascollected and dried in vacuo at 80° C. to yield 7.4 g. ofN,N-diethyl-6-methyl-2-(4pyridinyl)-4-pyrimidinamine dihydrochloride,m.p. 205°-208° C.

A-35. N,N-bis(2-Hydroxyethyl)-6-methyl-2-(4-pyridinyl)-pyrimidinamine -A solution containing 8.2 g. of4-chloro-6-methyl-2-(pyridinyl)pyrimidine, 12 g. ofbis(2-hydroxyethyl)amine and 100 ml. of ethanol was refluxed for fortyhours and the ethanol was then removed in vacuo. To the residue wasadded 100 ml. of water, the resulting cloudy solution was filtered andthe filtrate extracted with six 200 ml. portions of chloroform. Thechloroform solution was evaporated in vacuo to remove the chloroform andthe remaining solid was crystallized from isopropyl alcohol-ether toyield 7.5 g. ofN,N-bis(2-hydroxyethyl)-6-methyl-2-(4-pyridinyl)pyrimidinamine,m.p.135°-137° C.

A-36. tert.-Butyl N-[2-(4-pyridinyl)-4-pyrimidinyl]-carbamate isprepared following the procedure described in Example A-19 but using inplace of n-butyl chloroformate a molar equivalent quantity oftert.-butyl azido formate.

B. DI-(LOWER-ALKYL)[2-(PYRIDINYL)-4-PYRIMIDINYL]AMINO-METHYLENEMALONATES AND ANALOGS

B-1. Diethyl N-[2-(4-pyridinyl)-4-pyrimidinyl]amino-methylenemalonate -A mixture containing 108 g. of 4-amino-2-(4-pyridinyl)pyrimidine, 180 g.of diethyl ethoxymethylenemalonate and 300 ml. of xylene was heated withstirring in an oil bath at 190°-195° C. for seventy-two hours, whileallowing the ethanol (formed by the reaction) and xylene solvent toevaporate by using an air cooled condenser. The oily residue was treatedwith 500 ml. of ethanol followed by decolorizing charcoal. The mixturewas filtered and the filtrate evaporated to dryness in vacuo. Theresidue was crystallized from ethanol-ether to give 130 g. of diethylN-[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate, m.p. 138°-140°C. This compound was also prepared in the absence of a solvent asfollows: a mixture containing 100 g. of2-amino-4-(4-pyridinyl)pyrimidine and 190 g. of diethylethoxyaminomethylenemalonate was heated with stirring for twenty hoursat 135°-143° C. and was then allowed to cool slowly. Crystallizationstarted when the temperature was above 80° C. whereupon 100 ml. ofabsolute ethanol was added. The mixture was then allowed to cool to roomtemperature and the crystalline precipitate was collected, washed withcold ethanol and then ether. The resulting tan crystalline material wasrecrystallized from 400 ml. of absolute ethanol using decolorizingcharcoal to yield, as yellow crystals, 105 g. of diethylN-[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate, m.p. 143°-145°C. A 45 g. portion of this compound was dissolved in 225 mol. ofisopropyl alcohol, treated with decolorizing charcoal and filtered. Tothe filtrate was added one equivalent of concentrated hydrochloric acidwhereupon the crystallized hydrochloride separated immediately. Themixture was cooled and the product was collected, washed successivelywith cold isopropyl alcohol and ether, and dried in vacuo at 80° C. toyield 48 g. of diethylN-[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate hydrochloride,m.p. 227°-230° C. with decomposition.

B-2. Diethyl N-[2-(3-pyridinyl)-4-pyrimidinyl)]aminomethylenemalonate -A mixture containing 44 g. of 4-amino-2-(3-pyridinyl)pyrimidine and 55g. of diethyl ethoxymethylenemalonate was heated in an oil bath at160°-170° C. for three hours and then cooled to room temperature. Thereaction mixture was dissolved in methylene dichloride and the solutionfiltered thru a column of silica gel followed by elution of the columnwith 10% methanol in ether. Evaporation of the eluate yielded a yellowsolid which was recrystallized from ether-isopropyl alcohol to yield 45g. of diethyl N-[2-(3-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate,m.p. 115°-117° C.

B-3. Dimethyl N-[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate -A mixture containing 10 g. of 4-amino-2-(4-pyridinyl)pyrimidine, 10 g.of dimethyl methoxymethylenemalonate and 750 ml. of xylene was refluxedwith stirring for fourteen hours and then filtered to remove anyinsoluble reddish residue. The solution was evaporated to dryness; theresidue was dissolved in 400 ml. of 50-50 mixture (v/v) ofmethanol-chloroform; and, the solution was treated with decolorizingcharcoal and filtered. The filtrate was concentrated to a volume ofabout 200 ml. and was allowed to cool. The resulting yellow precipitatewas collected, washed with methanol and dried in vacuo to 80° C. to give14.2 g. of dimethylN-[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate, m.p. 209°-211°C.

B-4. Dimethyl N-[2-(3-pyridinyl)-4-pyrimidinyl]-aminomethylenemalonate -A mixture containing 8.6 g. of 4-amino-2-(3-pyridinyl)pyrimidine and 15g. of dimethyl ethoxymethylenenmalonate was heated in an oil bath at140°-150° C. for four hours. The reaction mixture was then dried invacuo and the remaining oily residue was dissolved in methanol. Themethanol solution was treated with decolorizing charcoal and filtered.The filtrate was chilled and the separated solid was collected and driedin vacuo at 80° C. to yield 11.8 g. of dimethylN-[2-(3-pyridinyl)-4-pyrimidinyl]-aminomethylenemalonate, m.p. 183°-184°C.

B-5. DiethylN-[6-methyl-2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate - Amixture containing 15.2 g. of 4-amino-6-methyl-2-(4-pyridinyl)pyrimidine and 25 ml. of diethyl ethoxymethylenemalonatewas heated with stirring at 150°-160° C. for two hours and then allowedto cool. The separated product was collected and crystallized frommethanol to yield 22.6 g. of diethylN-[6-methyl-2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate, m.p.169°-171° C.

Following the procedure described above in Example B-1 but using inplace of diethyl ethoxymethylenemalonate a molar equivalent quantity ofthe appropriate di-(lower-alkyl) lower-alkoxy)methylenemalonate, thecompounds of Examples B-6 through B-10 are obtained:

B-6. Di-n-propylN-[2-(4-pyridinyl)-4-pyrimidinyl]-aminomethylenemalonate usingdi-n-propyl n-propoxymethylenemalonate.

B-7. DiisopropylN-[2-(4-pyridinyl)-4-pyrimidinyl]-aminomethylenemalonate usingdiisopropyl isopropoxymethylenemalonate.

B-8. Di-n-butyl N-[2-(4-pyridinyl)-4-pyrimidinyl]-aminomethylenemalonateusing di-n-butyl n-butoxymethylenemalonate.

B-9. Diisobutyl N-[2-(4-pyridinyl)-4-pyrimidinyl]-aminomethylenemalonateusing diisobutyl ethoxymethylenemalonate.

B-10. Di-n-hexylN-[2-(4-pyridinyl)-4-pyrimidinyl]-aminomethylenemalonate usingdi-n-hexyl n-hexoxymethylenemalonate.

Following the procedures described in Example B-1 but using in place of4-amino-2-(4-pyridinyl)pyrimidine a molar equivalent quantity of theappropriate 4-amino-2-Q-pyrimidine, the compounds of Examples B-11through B-14 are obtained:

B-11. DiethylN-[2-(2-methyl-4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate using4-amino-2-(2-methyl-4-pyridinyl)pyrimidine. B-12. DiethylN-[2-(3-methyl-4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate using4-amino-2-(3-methyl-4-pyridinyl)pyrimidine.

B-13. DiethylN-[2-(2-ethyl-4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate using4-amino-2-(2-ethyl-4-pyridinyl)pyrimidine.

B-14. DiethylN-[2-(2,6-dimethyl-4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonateusing 4-amino-2-(2,6-dimethyl-4-pyridinyl)pyrimidine.

B-15. Diethyl N-[2-(2-pyridinyl)-4-pyrimidinyl]-aminomethylenemalonate -A mixture containing 8.7 g. of 4-amino-2-(2-pyridinyl)pyrimidine and14.2 g. of diethyl ethoxymethylenemalonate was heated in an oil bath at130°-140° C. for one hour and then cooled to room temperature. To thecooled reaction mixture was added with stirring 300 ml. of ether and themixture was filtered. To the filtrate was added 4.8 g. ofmethanesulfonic acid dissolved in 25 ml. of ethanol whereupon thereseparated an oily material which became a crystalline solid on standing.The solid was collected and recrystallized from ether-ethanol to yield10.4 g. of diethylN-[2-(2-pyridinyl)-4-pyrimidinyl]aminomethylenemalonatemethanesulfonate, m.p. 162°-164° C.

B-16. Diethyl N-[2-(4-pyridinyl)-4-pyrimidinyl]-aminomethylenemalonateN-Oxide - A mixture containing 5.2 g. of diethylN-[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate, 3.5 g. ofm-chloroperbenzoic acid (85%) and 125 ml. of methylene dichloride wasstirred in an ice bath for about one hour and then at room temperature(about 20°-25° C.) overnight (about 16 hours). An equal volume ofchloroform was added and this mixture was washed with aqueous sodiumbicarbonate solution. The organic layer was separated, dried overanhydrous magnesium sulfate and evaporated in vacuo to yield a yellowsolid. The solid was recrystallized from ethanol to yield 3.5 g. ofdiethyl N-[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate N-oxide,m.p. 198°-201° C. (started shrinking about 180° C.).

Alternatively, diethylN-[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate N-oxide isprepared following the procedure of Example B-1 using a molar equivalentquantity of 4-amino-2-(4-pyridinyl)pyrimidine N-oxide (see Example A-22for preparation) in place of 4-amino-2-(4-pyridinyl)pyrimidine.

B-17. Ethylα-{[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylene}acetoacetate(alternatively named ethyl3-oxo-2-{[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylene}butanoate) - Amixture containing 8.6 g. of 4-amino-2-(4-pyridinyl)pyrimidine, 13 g. ofethyl acetoacetate, 15 g. of triethyl orthoformate, 100 g. ofp-toluenesulfonic acid and 700 ml. of xylene was refluxed with stirringfor 92 hours, cooled to room temperature and then filtered. The filtratewas evaporated to dryness and the residue was dissolved in boilingethanolchloroform and the hot solution treated with decolorizingcharcoal and filtered. The filtrate was concentrated to about one-halfof its volume and then cooled. The separated solid was collected, washedwith ethanol and dried in vacuo at 80° C. to yield 7.2 g. of ethylα-{[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylene}acetoacetate, m.p.198°-200° C.

B-18. Ethylα-cyano-α-{[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylene}acetate(alternatively named ethyl2-cyano-3-{[2-(4-pyridinyl)-4-pyrimidinyl]amino}-2-propenoate) - Astirred mixture containing 10 g. of 4-amino-2-(4-pyridinyl)-pyrimidine,13 g. of ethyl α-cyano-α-ethoxymethyleneacetate and 700 ml. of xylenewas refluxed for 72 hours, treated with decolorizing charcoal andfiltered. The filtrate was evaporated to dryness and the yellowcrystalline solid residue was recrystallized twice from ethanol to yield9.3 g. of ethylα-cyano-α-{[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylene}acetate, m.p.195°-197° C.

B-19. Ethyl2-cyano-3-{[2-(4-pyridinyl)-4-pyrimidinyl]-amino}-2-butenoate - Amixture containing 8 g. of 4-amino-2-(4-pyridinyl)pyrimidine, 12 g. ofethyl 2-cyano-3-ethoxy-2-butenoate and 700 ml. of xylene was refluxedwith stirring for seventy-two hours. The reaction mixture was treatedwith decolorizing charcoal and filtered. The filtrate was evaporated invacuo to dryness. The residue was treated with methylene dichloride andthe insoluble starting amine was filtered off. The filtrate waschromotographed on a silica gel column (400 g.) using 20% methanol-ether(v/v) as the eluent. Evaporation in vacuo of the eluate yielded acrystalline material which was recrystallized from ethanol to yield 2.8g. of ethyl2-cyano-3-{[2-(4-pyridinyl)-4-pyrimidinyl]amino}-2-butenoate, m.p.203°-205° C.

B-20.3-<{[2-(4-Pyridinyl)-3-pyrimidinyl]amino}methylene>-2,4-pentanedione - Amixture containing 8.6 g. of 4-amino-2-(4-pyridinyl)pyrimidine, 10.7 g.of 2,4-pentanedione, 15 g. of triethyl orthoformate, 100 mg. ofp-toluenesulfonic acid monohydrate and 700 ml. of xylene was refluxedwith stirring for 98 hours, cooled to room temperature and filtered. Thefiltrate was evaporated in vacuo and the remaining residue was dissolvedin boiling ethanol, treated with decolorizing charcoal and the materialfiltered. The filtrate was concentrated and cooled. The remaining yellowcrystalline precipitate was collected, washed with ethanol and dried invacuo at 80° C. to yield 6.9 g. of3-<{[2-(4-pyridinyl)-3-pyrimidinyl]amino}methylene>-2,4-pentanedione,m.p. 182°-183° C.

B-21.2,2-Dimethyl-5-<{[2-(4-pyridinyl)-4-pyrimidinyl]-amino}-methyl>-1,3-dioxane-2,4-dione -A mixture containing 8.6 g. of 4-amino-2-(4-pyridinyl)pyrimidine, 15 g.of cyclic isopropylidene malonate, 15 g. of triethyl orthoformate, 100mg. of p-toluenesulfonic acid monohydrate and 700 ml. of xylene wasrefluxed with stirring for one-hundred and forty-four hours and cooled.The separated solid was collected, washed with ethanol andrecrystallized from dimethylformamide to yield 12 g. of2,2-dimethyl-5-<{[2-(4-pyridinyl)-4-pyrimidinyl]amino}-methyl>-1,3-dioxane-2,4-dione,m.p. 240° C. with decomposition.

B-22. DiethylN-[5-methyl-2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate isprepared following the procedure described in Example B-1 using a molarequivalent quantity of 4-amino-5-methyl-2-(4-pyridinyl)pyrimidine inplace of 4-amino-2-(4-pyridinyl)pyrimidine.

B-23. DiethylN-[6-n-propyl-2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate isprepared following the procedure described in Example B-1 using a molarequivalent quantity of 4-amino-5-n-propyl-2-(4-pyridinyl)pyrimidine inplace of 4-amino-2-(4-pyridinyl)pyrimidine.

B-24. N-[2-(4-Pyridinyl)-4-pyrimidinyl]aminomethylenemalonitrile isprepared following the procedure described in Example B-18 using a molarequivalent quantity of ethoxymethylenemalonitrile in place of ethylα-cyano-α-ethoxymethyleneacetate.

B-25. N-[2-(4-Pyridinyl)-4-pyrimidinyl]aminomethylenemalonamide isprepared following the procedure described in Example B-17 using a molarequivalent quantity of malonamide in place of ethyl acetoacetate.

B-26. α-{[2-(4-Pyridinyl)-4-pyrimidinyl]aminomethylene}acetoacetamide isprepared following the procedure described in Example B-17 using a molarequivalent quantity of acetoacetamide in place of ethyl acetoacetate.

B-27. Ethylα-carbamyl-α-{[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylene}acetate isprepared following the procedure described in Example B-17 using a molarequivalent quantity of ethyl α-carbamylacetate in place of ethylacetoacetate.

B-28.α-Cyano-α-{[2-(4-pyridinyl)-4-pyrimidinyl]-aminomethylene}acetamide isprepared following the procedure described in Example B-17 using a molarequivalent quantity of α-cyanoacetamide in place of ethyl acetoacetate.

B-29. Methylα-cyano-α-{[2-(4-pyridinyl)-4-pyrimidinyl]aminomethylene}acetate isobtained following the procedure described in Example B-17 using a molarequivalent quantity of methyl α-cyanoacetate in place of ethylacetoacetate.

B-30. 3-{[2-(4-Pyridinyl)-4-pyrimidinyl]amino}-2-propenenitrile - Amixture containing 17.2 g. of 4-amino-2-(4-pyridinyl)pyrimidine, 75 ml.of dimethyl sulfoxide, 4.8 g. of 57% sodium hydride and 12 ml. ofβ-ethoxyacrylonitrile was stirred at room temperature for five hours andthen poured into ice cold water. The separated solid was collected,washed with water, dried in vacuo at 80° C. and recrystallized fromdimethylformamide to produce 18.3 g. of3-{[2-(4-pyridinyl)-4-pyrimidinyl]amino}-2-propenenitrile, m.p.253°-255° C.

B-31. Methyl 3-{[2-(4-pyridinyl)-4-pyrimidinyl]amino}-2-propenoate isprepared following the procedure described in Example B-30 using a molarequivalent quantity of methyl β-methoxyacrylate in place ofβ-ethoxyacrylonitrile.

B-32. Ethyl 3-{[2-(4-pyridinyl)-4-pyrimidinyl]-amino}-2-propenoate isprepared following the procedure described in Example B-30 using a molarequivalent quantity of ethyl β-methoxyacrylate in place ofβ-ethoxyacrylonitrile.

B-33. 3-{[2-(4-Pyridinyl)-4-pyrimidinyl]amino}-2-propenamide is obtainedfollowing the procedure described in Example B-30 using a molarequivalent quantity of β-ethoxyacrylamide in place ofβ-ethoxyacrylonitrile.

B-34. DiethylN-[6-hydroxy-2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate isprepared following the procedure described in Example B-1 using a molarequivalent quantity of 4-amino-6-hydroxy-2-(4-pyridinyl)pyrimidine inplace of 4-amino-2-(4-pyridinyl)pyrimidine.

B-35. DiethylN-[6-hydroxy-5-methyl-2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonateis obtained following the procedure described in Example B-1 using amolar equivalent quantity of4-amino-6-hydroxy-5-methyl-2-(4-pyridinyl)pyrimidine in place of4-amino-2-(4-pyridinyl)pyrimidine.

B-36. DiethylN-[5-ethyl-6-hydroxy-2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonateis obtained following the procedure described in Example B-1 using amolar equivalent quantity of4-amino-5-ethyl-6-hydroxy-2-(4-pyridinyl)pyrimidine in place of4-amino-2-(4-pyridinyl)pyrimidine.

B-37. DiethylN-[6-chloro-5-ethyl-2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonateis obtained following the procedure described in Example A-5 using amolar equivalent quantity of diethylN-[5-ethyl-6-hydroxy-2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonatein place of 6-methyl-2-(4-pyridinyl)-4-pyrimidinol.

B-38. DiethylN-[5-ethyl-2-(4-pyridinyl)-4-pyrimidinyl]aminomethylenemalonate isobtained by reacting diethylN-[6-chloro-5-ethyl-2-(4-pyridinyl)-4-pyrimidinyl]-aminomethylenemalonatein absolute ethanol with 50 p.s.i. of hydrogen under catalytichydrogenation conditions using palladium-on-charcoal, thereby removingthe 6-chloro substituent of the starting material.

B-39. DiethylN-[5-cyano-2-(4-pyridinyl)-4-pyrimidinyl]-aminomethylenemalonate isobtained following the procedure described in Example B-1 using a molarequivalent quantity of 4-amino-5-cyano-2-(4-pyridinyl)pyrimidine [sameas 4-amino-2-(4-pyridinyl)-5-pyrimidinecarbonitrile] in place of4-amino-2-(4-pyridinyl)pyrimidine.

B-40. α-{[2-(4-Pyridinyl)-4-pyrimidinyl]aminomethylene}acetonitrile isobtained following the procedure described in Example B-17 using a molarequivalent quantity of acetoacetonitrile in place of ethyl acetoacetate.

B-41. N-[2-(4-Pyridinyl)-4-pyrimidinyl]-3-oxo-2-butenylamine is preparedfollowing the procedure described in Example B-30 using a molarequivalent quantity of methyl methoxyvinyl ketone of the formula CH₃OCH═CHCOCH₃ in place of β-ethoxyacrylonitrile.

The anti-allergic activity of the compounds of formulas I, II (exceptwhere Q' is halo), IV (as noted above) and V is determined by showingtheir effectiveness as inhibitors of release of mediators of allergicreactions by the IgE-mediated passive cutaneous anaphylaxis (PCA) methoddescribed as follows (IgE is the abbreviation for Immuno-globulin E, thecell-sensitizing antibody): Sprague-Dawley rats weighing 70 to 90 gramseach are injected intradermally with multiple serial dilutions of IgE 48hours before administration of the drug. The rats are fasted overnight(approximately seventeen hours) before the drug administration. Eachdrug being tested is administered orally at 100 mg./kg. to each of fourrats. Six other rats are observed as a control group. One hour afterdrug administration, 10 mg./kg. of egg albumen was administeredintravenously together with 17 mg./kg. of Evans Blue. Thirty minuteslater, the rats are killed by cervical fracture, the i.d. injected skinis everted, and the average of two perpendicular diameters of each bluearea is recorded. The average diameters vs. the reciprocal of thedilution of antibody in the control group is plotted on a semilog graph,and a best-fitting line is drawn through points for the control rats,and a best-fitting parallel line to the control line is drawn for eachtested drug. Comparative drug activity is evaluated by the degree of theshift to the right from controls, that is, by the ratio, R, of: ##EQU1##The results are interpreted as follows:

    ______________________________________                                        R(= degree of shift                                                                             Interpretation of                                           to the right      Drug Activity                                               ______________________________________                                        1.0 - 2.0         Inactive                                                    2 - 4             Weak                                                        4 - 8             Moderate                                                    >8                Strong                                                      ______________________________________                                    

When tested by the above procedure, said compounds of formulas I, II, IVand V as noted above were found to have R values >2, the more active andpreferred compounds having R values >8 and >10.

The more active and preferred compounds are further evaluated atmultiple doses, e.g., 100, 25, 6.2 and 1.6 mg./kg, by the IgE-mediatedPCA in rats. The test procedure for each dose is the same as givenabove, except for the interpretation of results. If two or more doses ofa compound have response lines (diameter vs. antibody dilution) that areparallel to each other and to controls, the potency of such a compoundis expressed by d(Ab)₃, that is, the dose of a drug that wouldnecessitate tripling of the concentration of antibody for the controlrats in order to achieve the same response line as for the medicatedrats. The d(Ab)₃ value is calculated as follows: The "R" values areplotted vs. the doses in mg./kg. on a log-log graph. A best fitting lineis drawn through the points, and a dose in mg./kg. corresponding to R=3is read as the d(Ab)₃. The hereinabove-noted preferred embodiments, whentested by said procedure, were found to have d(Ab)₃ values ranging fromabout 2 to 16, the lower the value the more active the compound.

The actual determination of the numerical antiallergic data definitivefor a particular compound of the invention is readily obtained accordingto the above-described standard test procedures by technicians versed inpharmacological test procedures, without any need for any extensiveexperimentation.

The compounds of the invention can be prepared for use by dissolvingunder sterile conditions a salt form of the compounds in water (or anequivalent amount of a nontoxic acid if the free base is used), or in aphysiologically compatible aqueous medium such as saline, and stored inampules for intramuscular injection. Alternatively, they can beincorporated in unit dosage form as tablets or capsules for oraladministration either alone or in combination with suitable adjuvantssuch as calcium carbonate, starch, lactose, talc, magnesium stearate,gum acacia, and the like. Also, the compounds can be formulated for oraladministration in aqueous alcohol, glycol or oil solutions or oil-wateremulsions in the same manner as conventional medicinal substances areprepared.

We claim:
 1. A compound of the formula ##STR13## where Q is 4- or 3- or2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkylsubstituents or N-oxide thereof, R₁ is hydrogen, lower-alkyl or cyano,R₂ is hydrogen, loweralkyl, hydroxy or halo, R₅ is hydrogen, lower-alkylor lower-hydroxyalkyl and R₆ is lower-alkyl or lower-hydroxyalkyl.